Risk Assessment of Inactive Ingredients in Generic Drug Formulations

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1 Risk Assessment of Inactive Ingredients in Generic Drug Formulations Elena Braithwaite, PhD, DABT FDA Office of Generic Drugs Division of Clinical Review 1

2 Disclaimer The opinions and information in this presentation are those of this presenter and do not represent the official views and/or policies of the United States Food and Drug Administration. 2

3 Outline 1. Challenges in evaluating inactive ingredients 2. Risk assessment procedure for evaluating inactive ingredients 3. Hypothetical example

4 Generic Drug Regulations Per 21 CFR , abbreviated new drug applications (ANDAs) may be submitted when the generic drug is the same as the reference listed drug (RLD), i.e., active ingredient(s) strength dosage form route of administration conditions of use Different inactive ingredients may be acceptable (21 CFR (a)(9)) Novel inactive ingredients are not acceptable in an ANDA submission. 4

5 Challenges in ensuring similar safety profiles in generics The goal is to ensure that differences in inactive ingredients do not change the risk profile of the generic compared to the RLD. Bioequivalence studies with a limited number of subjects are available for evaluation, e.g. PK study conducted in 30 subjects Typically, the OGD reviews toxicological summaries and clinical experience supported by published literature Often complete information on the excipient is not available 5

6 Risk Assessment Analysis 3 Step Process Nonclinical studies Clinical experience Risk compared to RLD 6

7 Risk Assessment Analysis 1st Step Nonclinical studies 7

8 Evaluating Nonclinical Studies (Part 1) International Conference on Harmonisation (ICH) and Code of Federal Regulations (CFR) Published literature NOAEL (no observed adverse effect level) the highest dose that does not produce a significant increase in adverse effects compared to controls LOAEL (lowest observed adverse effect level) the lowest tested concentration that results in an adverse effect(s)

9 Evaluating Nonclinical Studies (Part 2) How do we determine a safe level of human exposure in the absence of adequate clinical data? Calculate a human equivalent dose (HED) by: (Animal dose in mg/kg)/(species appropriate conversion factor) Dose (experimental animal) Conversion Factor Human Equivalent Dose (HED) 10 mg/kg (rat) mg/kg * 60 kg = 96.0 mg 9

10 Evaluating Nonclinical Studies (Part 3) Calculating an Acceptable Daily Intake (ADI) Apply safety factors ADI (human dose) = HED/Safety factor(s) Factor Description 10 Human Variability 10 Use of LOAEL HED = 1.6 mg/kg 1.6/10*10 = mg/kg ADI = mg/kg * 60 kg = 0.96 mg/day 10

11 Risk Assessment Analysis 2nd Step Nonclinical studies Clinical experience 11

12 Clinical Experience Consult the Inactive Ingredient Database Ingredient Route/dosage form Evaluate in the proper context Route of administration Target population Chronicity of use Indications for use 12

13 Risk Assessment Analysis 3rd Step Nonclinical studies Clinical experience Risk compared to RLD 13

14 Risk Compared to RLD Carefully examine the product labeling for: Adverse reactions Warnings and precautions Mechanism of action Consider off-label uses

15 Risk Assessment Analysis 3 Step Process Nonclinical studies Clinical experience Risk compared to RLD

16 Safe Uncertain Unsafe Excipient X Exposure 300 mg/day 100 mg/day HED (calculated from a LOAEL in dogs) Highest amount previously approved by the FDA (oral) 50 mg/day 30 mg/day 3 mg/day 0 mg/day Highest amount previously approved by the FDA (injectable) HED (calculated from a NOAEL in dogs) ADI - Safe level in humans set by use of safety factors RLD 16

17 Summary A scientifically based risk assessment procedure is used to evaluate inactive ingredients Risk assessment of inactive ingredients: Nonclinical studies Clinical experience Comparative risk profiling Using this procedure, inactive ingredients can be evaluated 17

18 Suggestions 1. A NOAEL is preferred when evaluating toxicological studies 2. Provide a completed Toxicology Data Summary Table with calculated ADI helps reviewers 3. Provide full pdf versions of all references cited 4. Published studies performed in rodent and non-rodent mammalian species are preferred 5. Do not include novel inactive ingredients in ANDA applications as their evaluation goes beyond the scope of an ANDA submission 18

19 Questions? Acknowledgements Sree Rayavarapu Bob Dorsam Lesley-Anne Furlong Brenda Gierhart Debra Catterson Deborah Seibel John Peters Zana Handy Marks James Osterhout In Ok Surh 19